Novel process

ABSTRACT

The invention relates to a process for the preparation of a compound of formula (V), according to the following scheme: wherein the various substituants are as defined in the description.

[0001] This invention relates to novel processes for the preparation of2-aminomethylpyridines (particularly2-aminomethyl-3-chloro-5-trifluoromethylpyridine), and for thepreparation of 2-cyanopyridines used in their preparation, whichcompounds are useful as intermediates for the production of pesticides.

[0002] The catalytic reduction of cyanopyridines to giveaminomethylpyridines is known. However when the cyanopyridine compoundcontain additional halogen atom(s) the reduction may be complicated bythe competing dehalogenation reaction. It is stated by P. N. Rylander,Hydrogenation Methods (Best Synthetic Series, published by AcademicPress), (1985), page 148, that palladium is usually the catalyst ofchoice when wishing to effect a dehalogenation reaction, and thatplatinum and rhodium are relatively ineffective and are hence often usedin hydrogenations where the halogen is to be preserved.

[0003] In contrast with the above prior art teaching we have found thatthe use of a palladium catalyst gives particularly good results in thereduction of cyanopyridines which contain additional halogen atom(s). Wehave developed a new process for the preparation of2-aminomethylpyridines, which contain additional halogen atom(s) inwhich minimal dehalogenation occurs, and which is applicable toindustrial scale processes.

[0004] There have been a number of procedures published for introducinga cyano group at the 2-position of a pyridine moiety. These typicallyinvolve substitution of a halogen, in particular bromine or fluorine, ina polar solvent, e.g. dimethyl sulphoxide or dimethylformamide. Inaddition, there are numerous methods starting from the activatedpyridine N-oxide or N-alkylpyridine. Many of these cyanation routes useheavy metal reagents, containing copper or nickel. For example,EP0034917 discloses the preparation of2-cyano-3-chloro-5-trifluoromethylpyridine from the 2-bromo analogue byreaction with cuprous cyanide in dimethylformamide at 120° C.

[0005] However, many of these prior art processes suffer from one ormore drawbacks, including poor yields, use of heavy metals which producetoxic effluents, or polar solvents which are difficult to recover.Further, methods which involve formation of the pyridine N-oxide orN-alkylpyridine involve several steps. These drawbacks are more criticalon scale-up to industrial scale.

[0006] GB Patent Publication Number 117970 describes the cyanation of2-halopyridine compounds with an activating agent and a cyanide sourcein a polar solvent and thus avoids many of the above disadvantages.However there still remains with this procedure the need to recycle theactivating agent and the aprotic solvent in order to minimise the costsfor an industrial scale process.

[0007] We have now developed an alternative and improved process for thepreparation of 2-cyanopyridines which is applicable to industrial scaleprocesses.

[0008] According to a first aspect of the present invention, there isprovided a process (A) for the preparation of a compound of generalformula (I):

[0009] or a salt thereof, which process comprises the catalytichydrogenation of a compound of general formula (II):

[0010] or a salt thereof,

[0011] wherein X is halogen; each Y, which may be the same or different,is halogen, haloalkyl, alkoxycarbonyl or alkylsulphonyl; and n is 0 to3.

[0012] In this invention halogen means a fluorine, chlorine or bromineatom. The preferred halogen atom is chlorine.

[0013] Haloalkyl typically means a C₁ to C₆ alkyl moiety substituted byone or more halogen atoms. For example the C₁ to C₆ alkyl moiety may bemethyl, ethyl, n-propyl or i-propyl, preferably methyl. The C₁ to C₆alkyl moiety is preferably substituted by one or more chlorine orfluorine atoms. A more preferred haloalkyl group is trifluoromethyl.

[0014] An alkoxycarbonyl group is typically C₁ to C₆ alkoxycarbonyl suchas methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl ori-propoxycarbonyl.

[0015] An alkylsulphonyl group is typically C₁ to C₆ alkylsulphonyl inwhich the C₁ to C₆ moiety is as defined above.

[0016] Preferably X is chlorine.

[0017] Preferably Y is halogen or haloalkyl (more preferablytrifluoromethyl).

[0018] Compound (II) is preferably3-chloro-2-cyano-5-trifluoromethylpyridine.

[0019] The catalyst generally comprises a metal selected from palladium,platinum, ruthenium, nickel and cobalt. The amount of metal in thecatalyst used (which is generally supported on for example charcoal) isgenerally from 0.05-0.7% by weight relative to the amount of thecompound of formula (II), preferably from 0.05-0.3%, more preferablyfrom 0.1-0.2%. A preferred catalyst contains palladium, for examplefinely divided palladium on an inert carrier such as charcoal. This hasbeen found to give both a convenient reaction rate and minimal sidereactions. Thus when the compound of formula (II) is3-chloro-2-cyano-5-trifluoromethylpyridine, minimal dechlorinationoccurs when using the process of the invention. Other examples ofsuitable catalysts include catalysts comprising oxides or othercompounds of the above mentioned metals.

[0020] The process is typically carried out in the presence of a solventsuch as an alcohol, for example methanol, ethanol, propanol or butanol,or an ester such as ethyl acetate, or an ether such as tetrahydrofuran.Alcohol solvents are preferred (methanol is most preferred). The processis preferably performed in the presence of a strong acid such ashydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid(preferably hydrochloric acid). The presence of the acid helps preventpoisoning of the catalyst by the amino group of the product of formula(I), and also prevents the coupling of amino intermediates which isotherwise known to occur during the catalytic hydrogenation of nitrites.

[0021] The reaction conditions typically comprise combining allreactants in a suitable reaction vessel and stirring, for example at atemperature of from 0 to 60° C., preferably from 20 to 30° C. A furtheradvantage of the process is that low pressures are used, with a hydrogenpressure of from 1 to 4 atmospheres generally being employed (theprocess is preferably performed at 1 atmosphere).

[0022] The reaction is optionally performed in the presence of acatalyst inhibitor, which can lead to a further improvement in thereaction selectivity by reducing the amount of dehalogenation which mayoccur as a side reaction. Such catalyst inhibitors are known in the art,for example as described in P. N. Rylander in Hydrogenation Methods(Best Synthetic Series, published by Academic Press), 1985, pages125-126, and include alkali metal bromides or iodides such as potassiumbromide and potassium iodide; or ammonium bromide or ammonium iodide; orhydrogen bromide or hydrogen iodide; or phosphorus compounds such astriphenyl phosphite, hypophosphorous acid, phosphorous acid oralkylphosphinic acids; or thiodiglycol (2,2′-thiodiethanol); orthiourea; or sulphur. Preferably the catalyst inhibitor is selected froman alkali metal bromide or iodide, ammonium bromide or iodide andhydrogen iodide.

[0023] The present invention thus provides a high yielding, selectiveand convenient process for the preparation of 2-aminomethylpyridines.

[0024] It is particularly convenient to generate the compound of formula(I) in the form of a salt, especially a hydrochloride salt. When used asan intermediate in the production of a pesticide the salt can besubmitted directly to the next reaction step without prior isolation ofthe corresponding free amine. The production of the salt and itssubsequent reaction can therefore be conveniently carried out in asingle vessel. A particularly preferred salt is2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride.

[0025] According to a further feature of the present invention, there isprovided a process (B) for the preparation of a compound of generalformula (II) as defined above which comprises treating a compound ofgeneral formula (III):

[0026] with a cyanide source and a catalyst in an aqueous solvent orwithout solvent,

[0027] wherein X, Y and n are as hereinbefore defined; and wherein thecyanide source is hydrogen cyanide, an alkali metal cyanide, an alkalineearth metal cyanide or an optionally substituted ammonium cyanide.

[0028] The catalyst is generally a phase transfer catalyst such as atetraalkyl ammonium salt such as benzyl trimethylammonium chloride,tricaprylylmethylammonium chloride, tetramethylammonium chloride,tetra-n-propylammonium bromide, n-dodecyl trimethylammonium chloride,tetra-n-butylammonium chloride, tetra-n-butylammonium bromide,tetra-n-octylammonium bromide or n-tetradecyl trimethylammonium bromide;or a tetraalkyl phosphonium salt such as tetra-n-butylphosphoniunbromide or tetraphenylphosphonium bromide; or a crown ether or acyclicanalogue thereof such as TDA-1 (tris[2-(2-methoxyethoxy)ethyl]amine); oran amine such as 4-dimethylaminopyridine.

[0029] Preferably the catalyst is selected fromtricaprylylmethylammonium chloride and tetra-n-octylammonium bromide.

[0030] The amount of catalyst used is generally from about 0.01 to 10mol %, preferably from about 0.1 to 5 mol %, more preferably from about1 to 5 mol %.

[0031] Compound (III) is preferably3-chloro-2-fluoro-5-trifluoromethylpyridine.

[0032] The above process (B) of the invention is a high yielding processfor the preparation of 2-cyanopyridines, which is simple to perform andoperates at moderate temperatures and does not suffer from the drawbacksof many prior art processes. In particular the process of the inventiondoes not require heavy metal cyanides such as copper or nickel cyanide,which, when used on an industrial scale, produce toxic effluent streamsand are difficult to recover. The process (B) of the invention produceswaste streams, which are readily treatable.

[0033] In addition, the process does not require the preparation ofactivated pyridine N-oxide or N-alkylpyridine for high conversions,which is a requisite for many of the prior art processes. The process(B) of the invention does not require an activating agent such as4-dimethylaminopyridine and hence avoids additional recovery andrecycling steps. A further advantage of the process (B) of the inventionis that organic solvents are not used in the reaction, thus avoiding theneed to recycle expensive solvents such as dimethyl sulphoxide.

[0034] The cyanide source is preferably sodium cyanide or potassiumcyanide, preferably potassium cyanide. The amount of cyanide source usedis generally from about 1.0 to about 2.0 molar equivalents (however moremay be used if desired), preferably from 1.0 to 1.5 molar equivalents,more preferably from 1.0 to 1.1 molar equivalents.

[0035] The reaction is generally and preferably performed using water assolvent, however it may also be carried out in the absence of solvent.

[0036] The reaction conditions typically comprise combining allreactants in a suitable reaction vessel and stirring at a temperature offrom 10 to 60° C., preferably from 20 to 40° C.

[0037] The present invention thus provides a high yielding process (B)for the preparation of 2-cyanopyridines. Since the reaction usesmoderate reaction temperatures, simple and inexpensive reactors anddownstream processing equipment is all that is required. Furthermore,since the reactants are readily available, the process is inexpensive tooperate. In addition, the present process produces waste streams thatare readily treatable.

[0038] According to a further feature of the invention the processes (B)and (A) can be combined to prepare a compound of formula (I) from acompound of formula (III).

[0039] According to a further feature of the invention the process (A),or the combined processes (B) and (A), is followed by a further processstep (C) which comprises the acylation of said compound (I) with abenzoyl compound of formula (IV):

[0040] wherein L is a leaving group; R¹ and R² each represent the sameor different halogen; and m is 0, 1 or 2, to give a compound of formula(V):

[0041] Preferably L is chlorine.

[0042] Compounds of Formula (V) are valuable pesticide activeingredients disclosed for example in International Patent PublicationNumber WO 99/42447.

[0043] Preferred compounds of formula (V) are:

[0044]N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,6-dichlorobenzamide;

[0045]N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,6-difluorobenzamide;

[0046]N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-chloro-6-fluorobenzamide;

[0047]N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,3-difluorobenzamide;

[0048]N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,4,6-trifluorobenzamideor

[0049]N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-bromo-6-chlorobenzamide.

[0050] Process step (C) is described in International Patent PublicationNumber WO 99/42447.

[0051] According to a further feature of the invention the process (B),or the combined processes (B) and (A), or (B), (A) and (C) can becombined with an earlier process step (D) which comprises thefluorination of a compound of formula (VI):

[0052] wherein X, Y and n are as defined above.

[0053] The process step (D) is generally performed using a suitablefluorinating agent such as an alkali metal fluoride, preferablypotassium fluoride or sodium fluoride, in an aprotic solvent such asdimethyl sulphoxide or sulpholane, at a temperature of from 50° C. to150° C.

[0054] The compounds of formula (I) and (II) obtained by the aboveprocesses of the invention are particularly useful in the preparation offungicidally active 2-pyridylmethylamine derivatives of formula (V),according to the following reaction scheme:

[0055] The present invention is further illustrated by the followingpreparative examples:

EXAMPLE 1 (PROCESS STEP A)

[0056] A mixture of 3-chloro-2-cyano-5-trifluoromethylpyridine (5.1 g)and 5% palladium on charcoal (5.1 mg as Pd metal) was stirred at 20° C.with methanol and concentrated hydrochloric acid (2.5 ml) under 1atmosphere of hydrogen. After 4 hours the reaction was judged to becomplete by hplc. The mixture was filtered through Celatom, washed withmethanol and water and evaporated to give2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride in 95-97%yield, NMR (in D₂O) 4.6 (s, 2H), 8.35 (s, 1H), 8.9 (s, 1H).

EXAMPLE 2 (PROCESS STEP B)

[0057] A solution of potassium cyanide (71.6 g) in water (215 g) wasadded during 1 hour to a stirred mixture of3-chloro-2-fluoro-5-trifluoromethylpyridine (199.5 g) and Aliquat 336(tricaprylylmethylammonium chloride, 12.1 g) at 30° C. Stirring wasmaintained at this temperature for 4 hours at which time the amount ofstarting fluoride was less than 1% by hplc. The lower organic phase wasseparated and washed with aqueous sodium chloride solution and distilledto give 3-chloro-2-cyano-5-trifluoromethylpyridine (185.8 g, 90% yield)bp 90° C. at 15 mbar. The purity of this product was 98%.

EXAMPLE 3 (PROCESS STEP B)

[0058] Solid sodium cyanide (0.29 g) was added to a stirred mixture of3-chloro-2-fluoro-5-trifluoromethylpyridine (0.8 g) andtetrabutylammonium bromide (0.06 g) at 20-25° C., and stirred for 23hours to give 3-chloro-2-cyano-5-trifluoromethylpyridine (0.68 g, 82%yield by hplc).

EXAMPLE OF PROCESS STEP (D)

[0059] 2,3-Dichloro-5-trifluoromethylpyridine (800 g) was added to astirred mixture of anhydrous potassium fluoride (320 g) and anhydrousdimethylsulphoxide at 110° C. then heated at 120° C. for 2 hours andfractionally distilled under reduced pressure to give3-chloro-2-fluoro-5-trifluoromethylpyridine (685 g) in a yield of 92%(98% purity).

1. A process for the preparation of a compound of general formula (I):

or a salt thereof, which process comprises the catalytic hydrogenation of a compound of general formula (II):

or a salt thereof, wherein X is halogen; each Y, which may be the same or different, is halogen, haloalkyl, alkoxycarbonyl or alkylsulphonyl; and n is 0 to
 3. 2. A process according to claim 1 in which X is chlorine.
 3. A process according to claim 1 or 2 in which Y is halogen or haloalkyl.
 4. A process according to claim 3 in which Y is trifluoromethyl.
 5. A process according to claims 1 to 4 in which the catalyst comprises a metal selected from palladium, platinum, ruthenium, nickel and cobalt.
 6. A process according to claims 1 to 5 in which the catalyst is palladium.
 7. A process according to claim 5 or 6 in which the amount of metal in the catalyst is from 0.05-0.7% by weight relative to the amount of the compound of formula (I).
 8. A process according to claim 5 or 6 or 7 in which the amount of metal in the catalyst is from 0.05-0.3% by weight relative to the amount of the compound of formula (II).
 9. A process according to claim 5 or 6 or 7 or 8 in which the amount of metal in the catalyst is from 0.1-0.2% by weight relative to the amount of the compound of formula (II).
 10. A process according to any one of the preceding claims which is conducted in the presence of an alcohol solvent.
 11. A process according to claim 10 in the alcohol solvent is methanol.
 12. A process according to any one of the preceding claims which is performed at 0 to 60° C.
 13. A process according to any one of the preceding claims which is performed at a hydrogen pressure of from 1 to 4 atmospheres.
 14. A process according to any one of the preceding claims which is performed in the presence of a catalyst inhibitor.
 15. A process according to claim 14 in which the catalyst inhibitor is selected from an alkali metal bromide or iodide, ammonium bromide or iodide and hydrogen bromide or iodide.
 16. A process according to any one of the preceding claims in which the compound of formula (II) is 3-chloro-2-cyano-5-trifluoromethylpyridine.
 17. A process for the preparation of a compound of general formula (II) as defined in any one of claims 1 to 4, which process comprises treating a compound of general formula (III):

with a cyanide source and a catalyst in an aqueous solvent or without solvent, wherein: X, Y and n are as defined in claim 1; and wherein the cyanide source is hydrogen cyanide, an alkali metal cyanide, an alkaline earth metal cyanide or an optionally substituted ammonium cyanide.
 18. A process according to claim 17 in which the catalyst is a phase transfer catalyst; or a crown ether or acyclic analogue thereof; or an amine.
 19. A process according to claim 17 or 18 in which the catalyst is a tetraalkyl ammonium salt or a tetraalkyl phosphonium salt.
 20. A process according to claim 17, 18 or 19 in which the catalyst is selected from tricaprylylmethylammonium chloride and tetra-n-octylammonium bromide.
 21. A process according to any one of claims 17 to 20 in which the amount of catalyst used is from 0.01 to 10 mol %.
 22. A process according to any one of claims 17 to 21 in which the cyanide source is potassium cyanide.
 23. A process according to any one of claims 17 to 22 in which the amount of cyanide source used is from 1.0 to 2.0 molar equivalents.
 24. A process according to any one of claims 17 to 23 in which the solvent is water.
 25. A process according to any one of claims 17 to 24 in which the temperature is from 10 to 60° C.
 26. A process according to any one of claims 17 to 25 in which the compound of formula (III) is 3-chloro-2-fluoro-5-trifluoromethylpyridine.
 27. A process according to any one of claims 17 to 26, which is followed by a process according to any one of claims 1 to
 16. 28. A process according to any one of claims 1 to 16 or 27, which is followed by a further process step which comprises the acylation of said compound (I) with a benzoyl compound of formula (IV):

wherein L is a leaving group; R¹ and R² each represent the same or different halogen; and m is 0, 1 or 2, to give a compound of formula (V):


29. A process according to claim 17, 27 or 28 which is combined with an earlier process step which comprises the fluorination of a compound of formula (VI):

wherein X, Y and n are as defined above.
 30. A process according to any one of the preceding claims in which X is chlorine.
 31. A compound of formula (I) when produced by a process as defined in any one of claims 1, 27 or
 30. 32. A compound which is 2-aminomethyl-3-chloro-5-trifluoromethyl-pyridine hydrochloride.
 33. A compound of formula (II) when produced by a process as defined in claim 17 or
 29. 34. A compound of formula (V) when produced by a process as defined in claim 28 or
 29. 35. A compound according to claim 34 which is: N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,6-dichlorobenzamide; N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,6-difluorobenzamide; N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-chloro-6-fluorobenzamide; N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,3difluorobenzamide; N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,4,6-trifluorobenzamide or N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-bromo-6-chlorobenzamide.
 36. A process for the preparation of compounds of formula (V), characterised by the following scheme: 